Cancers of the brain and nervous system are among the most difficult to treat. Prognosis for patients with these cancers depends on the type and location of the tumor as well as its stage of development. For many types of brain cancer, average life expectancy after symptom onset may be months or a year or two. Treatment consists primarily of surgical removal and radiation therapy; chemotherapy is also used, but the range of suitable chemotherapeutic agents is limited, perhaps because most therapeutic agents do not penetrate the blood-brain barrier adequately to treat brain tumors. Using known chemotherapeutics along with surgery and radiation rarely extends survival much beyond that produced by surgery and radiation alone. Thus improved therapeutic options are needed for brain tumors.
Gliomas are a common type of brain tumor. They arise from the supportive neuronal tissue comprised of glial cells (hence the name glioma), which maintain the position and function of neurons. Gliomas are classified according to the type of glial cells they resemble: astrocytomas (including glioblastomas) resemble star-shaped astrocyte glial cells, oligodendrogliomas resemble oligodendrocyte glial cells; and ependymomas resemble ependymal glial cells that form the lining of fluid cavities in the brain. In some cases, a tumor may contain a mixture of these cell types, and would be referred to as a mixed glioma.
The typical current treatment for brain cancers is surgical removal of the majority of the tumor tissue, which may be done by invasive surgery or using biopsy or extractive methods. Gliomas tend to disseminate irregularly, though, and are very difficult to remove completely. As a result, recurrence nearly always occurs soon after tumor removal. Radiation therapy and/or chemotherapy can be used in combination with surgical removal, but these generally provide only modest extension of survival time. For example, recent statistics showed that only about half of patients in the U.S. who are diagnosed with glioblastoma are alive one year after diagnosis, and only about 25% are still alive after two years, even when treated with the current standard of care combination treatments.
Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is notorious for its lethality and lack of responsiveness to current treatment approaches. Unfortunately, there have been no substantial improvements in treatment options in recent years, and minimal improvements in the survival prospects for patients with GBM. Thus there remains an urgent need for improved treatments for cancers of the brain such as gliomas.
Gliomas develop in a complex tissue microenvironment comprised of many different types of cells in the brain parenchyma in addition to the cancer cells themselves. Tumor-associated macrophages (TAMs) are one of the prominent stromal cell types present, and often account for a substantial portion of the cells in the tumor tissues. Their origin is not certain: these TAMs may originate either from microglia, the resident macrophage population in the brain, or they may be recruited from the periphery.
TAMs can modulate tumor initiation and progression in a tissue-specific manner: they appear to suppress cancer development in some cases, but they enhance tumor progression in the majority of studies to date. Indeed, in approximately 80% of the cancers in which there is increased macrophage infiltration, the elevated TAM levels are associated with more aggressive disease and poor patient prognosis. Several studies have shown that human gliomas also exhibit a significant increase in TAM numbers, which correlates with advanced tumor grade, and TAMs are typically the predominant immune cell type in gliomas. However, the function of TAMs in gliomagenesis remains poorly understood, and it is currently not known whether targeting of these cells represents a viable therapeutic strategy. In fact, opposing effects on tumor growth have been reported in the literature, in some cases even where a similar experimental strategy was used to deplete macrophages in the same orthotopic glioma implantation model. In some studies, TNF-α or integrin β3 produced by TAMs have been implicated in the suppression of glioma growth, whereas in other reports CCL2 and MT1-MMP have been proposed as enhancers of tumor development and invasion.
Inhibition of CSF-1R signaling represents a novel, translationally relevant approach that has been used in several oncological contexts, including xenograft intratibial bone tumors. However, it has not yet been shown to be effective in brain tumors. Some non-brain cancers have been targeted with compounds that affect a variety of cell types that are associated with, or support, tumor cells rather than directly targeting the tumor cells themselves. For example, PLX3397 is reported to co-inhibit three targets (FMS, Kit, and Flt3-ITD) and to down-modulate various cell types including macrophages, microglia, osteoclasts, and mast cells. PLX3397 has been tested for treating Hodgkin's lymphoma. However, Hodgkin's lymphoma responds well to various chemotherapeutics, according to the PLX3397 literature, while brain tumors are much more resistant to chemotherapeutics and have not been successfully treated. As demonstrated herein, a CSF-1R inhibitor had no direct effect on proliferation of glioblastoma cells in culture, though, and it did not reduce numbers of macrophage cells in tumors of treated animals. It is thus surprising that, as also demonstrated herein, a CSF-1R inhibitor can effectively inhibit growth of brain tumors in vivo, cause reduction in tumor volume in advanced stage GBM, and even apparently eradicating some glioblastomas.